Effective neuroprotective therapy for acute ischemic stroke remains an elusive goal despite substantial research into the mechanism of ischemic neuronal injury and demonstration of robust efficacy of many candidate drugs in animal models. The reasons for clinical failure are manifold, but most authorities identify drug toxicity, short time window for therapeutic effect following ischemic onset, and weak biological effect of individual agents among the primary deficiencies of drugs studied to date. Here, we propose further study of a safe, widely consumed combination of "drugs" (low doses of caffeine and ethanol), which in preliminary studies have demonstrated an interactive positive effect (while, either drug alone has any beneficial effect), with more robust activity and a longer time window for efficacy than any other neuroprotective therapy tried in our laboratory over the past decade. Our study will be carried out in rats with transient MCA/CCA occlusion and has two specific aims: 1). To determine the effects on infarct volume and motor function of varying the dosing, timing, and duration of treatment, and to explore the tolerance to chronic use of this drug combination. Our hypothesis is that the most effective approach will be a single relatively low dose of the combination that can be given up to 2 hours after stroke onset producing blood levels that can be easily and safely achieved in humans. 2). To identify the targets for the pharmacologic effect of the caffeine/ethanol combination by examining the effect of caffeine plus ethanol on cerebral blood flow and on excitotoxic cortical lesions by substituting drugs which specifically affect adenosine, NMDA, and GABA receptors, and by investigating the effect of the combination on excitatory and inhibitory amino acids and adenosine using microdialysis. Our hypothesis is that the neuroprotective effect of the caffeine/ethanol combination will be associated with inhibition of adenosine and postsynaptic glutamate receptors and activation of the GABA- ergic pathway producing and optimal balance between excitation/inhibition resulting in protection of penumbral brain regions. This study should provide the necessary information to translate our experimental results with this novel and potentially useful drug combination to clinical therapeutic trials in human stroke patients.